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Modulation of DOM-Induced Head-Twitch Response by mGluR2 Agonist/Inverse Agonist is Associated with 5-HT2AR-Mediated Gs Signaling Pathway

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Abstract

Hallucinogenic 5-HT2A receptor (5-HT2AR) agonists-induced head-twitch response (HTR) is regulated by Gs signaling pathway. Formation of heterodimers between 5-HT2AR and metabotropic glutamate mGlu2 receptor (mGluR2) is essential for the hallucinogenic 5-HT2AR agonist-induced HTR. In order to investigate the effects of mGluR2 agonists and inverse agonists on hallucinogenic 5-HT2AR agonists DOM-induced HTR, C57BL/6 mice were pretreated with mGluR2 agonists (LY379268, LY354740, LY404039) or the inverse agonist LY341495, and the HTR was manually counted after administering DOM immediately. IP-One (IP1) HTRF assay and cAMP assay were performed to evaluate the effect of LY341495 or LY354740 on DOM-induced Gq and Gs activation in Human Embryonic Kidney-293 (HEK-293) T-type cells co-expressing 5-HT2AR and mGluR2. The results showed that DOM-induced HTR in mice was dose-dependently inhibited by LY379268, LY354740, and LY404039, while it was dose-dependently enhanced by LY341495. Moreover, LY341495 reversed the inhibitory effect of LY354740 on DOM-induced HTR. In HEK-293T cells co-expressing 5-HT2AR and mGluR2, DOM-induced cAMP level was decreased by LY354740 and increased by LY341495, but DOM-induced IP1 level was not regulated by LY354740 or LY341495. The regulation of DOM-induced HTR by mGluR2 agonists and inverse agonists is closely related to 5-HT2AR-mediated Gs signaling pathway. In HEK-293T cells co-expressing 5-HT2AR and mGluR2 A677S/A681P/A685G mutant (mGluR2 3 A mutant), DOM-induced cAMP level was not regulated by LY354740, but was significantly enhanced by LY341495. The 5-HT2AR/mGluR2 heterodimers is critical for DOM-induced HTR and cAMP level, both of which are inhibited by mGluR2 agonists and enhanced by mGluR2 inverse agonists.

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References

  1. Shah UH, Gonzalez-Maeso J (2019) Serotonin and glutamate interactions in preclinical schizophrenia models. ACS Chem Neurosci 10:3068–3077

    Article  CAS  PubMed  Google Scholar 

  2. Watkins JC (2000) l-glutamate as a central neurotransmitter: looking back. Biochem Soc Trans 28:297–309

    Article  CAS  PubMed  Google Scholar 

  3. Wischhof L, Koch M (2016) 5-HT2A and mGlu2/3 receptor interactions: on their relevance to cognitive function and psychosis. Behav Pharmacol 27:1–11

    Article  CAS  PubMed  Google Scholar 

  4. Chaki S (2019) mGlu2/3 receptor antagonists. Adv Pharmacol 86:97–120

    Article  CAS  PubMed  Google Scholar 

  5. Chaki S, Fukumoto K (2019) Role of serotonergic system in the antidepressant actions of mGlu2/3 receptor antagonists: similarity to ketamine. Int J Mol Sci 20:1270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Marek GJ, Wright RA, Schoepp DD, Monn JA, Aghajanian GK (2000) Physiological antagonism between 5-hydroxytryptamine(2A) and group II metabotropic glutamate receptors in prefrontal cortex. J Pharmacol Exp Ther 292:76–87

    CAS  PubMed  Google Scholar 

  7. González-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV, López-Giménez JF, Zhou M, Okawa Y, Callado LF, Milligan G, Gingrich JA, Filizola M, Meana JJ, Sealfon SC (2008) Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature 452:93–97

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  8. Toneatti R, Shin JM, Shah UH, Mayer CR, Saunders JM, Fribourg M, Arsenovic PT, Janssen WG, Sealfon SC, Lopez-Gimenez JF, Benson DL, Conway DE, Gonzalez-Maeso J (2020) Interclass GPCR heteromerization affects localization and trafficking. Sci Signal 13:eaaw3122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Moreno JL, Muguruza C, Umali A, Mortillo S, Holloway T, Pilar-Cuellar F, Mocci G, Seto J, Callado LF, Neve RL, Milligan G, Sealfon SC, Lopez-Gimenez JF, Meana JJ, Benson DL, Gonzalez-Maeso J (2012) Identification of three residues essential for 5-hydroxytryptamine 2A-metabotropic glutamate 2 (5-HT2A.mGlu2) receptor heteromerization and its psychoactive behavioral function. J Biol Chem 287:44301–44319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gonzalez-Maeso J, Weisstaub NV, Zhou M, Chan P, Ivic L, Ang R, Lira A, Bradley-Moore M, Ge Y, Zhou Q, Sealfon SC, Gingrich JA (2007) Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior. Neuron 53:439–452

    Article  CAS  PubMed  Google Scholar 

  11. Jiang K, Liu X, Su R (2022) Contrasting effects of DOI and lisuride on impulsive decision-making in delay discounting task. Psychopharmacology 239:3551–3565

    Article  CAS  PubMed  Google Scholar 

  12. Karaki S, Becamel C, Murat S, Mannoury la Cour C, Millan MJ, Prezeau L, Bockaert J, Marin P, Vandermoere F (2014) Quantitative phosphoproteomics unravels biased phosphorylation of serotonin 2A receptor at Ser280 by hallucinogenic versus nonhallucinogenic agonists. Mol Cell Proteomics 13:1273–1285

    Article  CAS  Google Scholar 

  13. Nichols DE (2016) Psychedelics. Pharmacol Rev 68:264–355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Moreno JL, Holloway T, Albizu L, Sealfon SC, Gonzalez-Maeso J (2011) Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists. Neurosci Lett 493:76–79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. de la Fuente Revenga M, Shin JM, Vohra HZ, Hideshima KS, Schneck M, Poklis JL, Gonzalez-Maeso J (2019) Fully automated head-twitch detection system for the study of 5-HT2A receptor pharmacology in vivo. Sci Rep 9:14247

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  16. Klodzinska A, Bijak M, Tokarski K, Pilc A (2002) Group II mGlu receptor agonists inhibit behavioural and electrophysiological effects of DOI in mice. Pharmacol Biochem Behav 73:327–332

    Article  CAS  PubMed  Google Scholar 

  17. Aghajanian GK, Marek GJ (1997) Serotonin induces excitatory postsynaptic potentials in apical dendrites of neocortical pyramidal cells. Neuropharmacology 36:589–599

    Article  CAS  PubMed  Google Scholar 

  18. Zhai Y, George CA, Zhai J, Nisenbaum ES, Johnson MP, Nisenbaum LK (2003) Group II metabotropic glutamate receptor modulation of DOI-induced c-fos mRNA and excitatory responses in the cerebral cortex. Neuropsychopharmacology 28:45–52

    Article  CAS  PubMed  Google Scholar 

  19. Fribourg M, Moreno JL, Holloway T, Provasi D, Baki L, Mahajan R, Park G, Adney SK, Hatcher C, Eltit JM, Ruta JD, Albizu L, Li Z, Umali A, Shim J, Fabiato A, MacKerell AD Jr, Brezina V, Sealfon SC, Filizola M, Gonzalez-Maeso J, Logothetis DE (2011) Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic Drugs. Cell 147:1011–1023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Liu X, Zhu H, Gao H, Tian X, Tan B, Su R (2022) Gs signaling pathway distinguishes hallucinogenic and nonhallucinogenic 5-HT2AR agonists induced head twitch response in mice. Biochem Biophys Res Commun 598:20–25

    Article  CAS  PubMed  Google Scholar 

  21. Benvenga MJ, Chaney SF, Baez M, Britton TC, Hornback WJ, Monn JA, Marek GJ (2018) Metabotropic glutamate2 receptors play a key role in modulating head twitches induced by a serotonergic hallucinogen in mice. Fronti Pharmacol 9:208

    Article  Google Scholar 

  22. Gewirtz JC, Marek GJ (2000) Behavioral evidence for interactions between a hallucinogenic drug and group II metabotropic glutamate receptors. Neuropsychopharmacology 23:569–576

    Article  CAS  PubMed  Google Scholar 

  23. Knudsen GM (2023) Sustained effects of single doses of classical psychedelics in humans. Neuropsychopharmacology 48:145–150

    Article  CAS  PubMed  Google Scholar 

  24. Nichols DE (2004) Hallucinogens. Pharmacol Ther 101:131–181

    Article  CAS  PubMed  Google Scholar 

  25. Canal CE, Morgan D (2012) Head-twitch response in rodents induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine: a comprehensive history, a re-evaluation of mechanisms, and its utility as a model. Drug Test Anal 4:556–576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Halberstadt AL, Geyer MA (2013) Characterization of the head-twitch response induced by hallucinogens in mice: detection of the behavior based on the dynamics of head movement. Psychopharmacology 227:727–739

    Article  CAS  PubMed  Google Scholar 

  27. Moreno JL, Holloway T, Rayannavar V, Sealfon SC, Gonzalez-Maeso J (2013) Chronic treatment with LY341495 decreases 5-HT(2A) receptor binding and hallucinogenic effects of LSD in mice. Neurosci Lett 536:69–73

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Halberstadt AL, van der Zee JVF, Chatha M, Geyer MA, Powell SB (2019) Chronic treatment with a metabotropic mGlu2/3 receptor agonist diminishes behavioral response to a phenethylamine hallucinogen. Psychopharmacology 236:821–830

    Article  CAS  PubMed  Google Scholar 

  29. Rorick-Kehn LM, Johnson BG, Burkey JL, Wright RA, Calligaro DO, Marek GJ, Nisenbaum ES, Catlow JT, Kingston AE, Giera DD, Herin MF, Monn JA, McKinzie DL, Schoepp DD (2007) Pharmacological and pharmacokinetic properties of a structurally novel, potent, and selective metabotropic glutamate 2/3 receptor agonist: in vitro characterization of agonist (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic acid (LY404039). J Pharmacol Exp Ther 321:308–317

    Article  CAS  PubMed  Google Scholar 

  30. Fell MJ, Svensson KA, Johnson BG, Schoepp DD (2008) Evidence for the role of metabotropic glutamate (mGlu)2 not mGlu3 receptors in the preclinical antipsychotic pharmacology of the mGlu2/3 receptor agonist (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY404039). J Pharmacol Exp Ther 326:209–217

    Article  CAS  PubMed  Google Scholar 

  31. Delille HK, Mezler M, Marek GJ (2013) The two faces of the pharmacological interaction of mGlu2 and 5-HT(2)A - relevance of receptor heterocomplexes and interaction through functional brain pathways. Neuropharmacology 70:296–305

    Article  CAS  PubMed  Google Scholar 

  32. Garcia EE, Smith RL, Sanders-Bush E (2007) Role of G(q) protein in behavioral effects of the hallucinogenic drug 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane. Neuropharmacology 52:1671–1677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Albizu L, Holloway T, Gonzalez-Maeso J, Sealfon SC (2011) Functional crosstalk and heteromerization of serotonin 5-HT2A and dopamine D2 receptors. Neuropharmacology 61:770–777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Vinals X, Moreno E, Lanfumey L, Cordomi A, Pastor A, de La Torre R, Gasperini P, Navarro G, Howell LA, Pardo L, Lluis C, Canela EI, McCormick PJ, Maldonado R, Robledo P (2015) Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors. PLoS Biol 13:e1002194

    Article  PubMed  PubMed Central  Google Scholar 

  35. Halberstadt AL, Lehmann-Masten VD, Geyer MA, Powell SB (2011) Interactive effects of mGlu5 and 5-HT2A receptors on locomotor activity in mice. Psychopharmacology 215:81–92

    Article  CAS  PubMed  Google Scholar 

  36. Doherty MD, Pickel VM (2000) Ultrastructural localization of the serotonin 2A receptor in dopaminergic neurons in the ventral tegmental area. Brain Res 864:176–185

    Article  CAS  PubMed  Google Scholar 

  37. Mato S, Aso E, Castro E, Martin M, Valverde O, Maldonado R, Pazos A (2007) CB1 knockout mice display impaired functionality of 5-HT1A and 5-HT2A/C receptors. J Neurochem 103:2111–2120

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing, China

    Huan Gao, Xiaoqian Liu, Lulu Xie, Bo Tan & Ruibin Su

  2. School of Pharmacy, Yantai University, Yantai, China

    Huan Gao

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RS and BT: Conceptualization; HG and XL: methodology; HG and LX: experiment; HG and BT: writing—original draft preparation and review; RS: funding acquisition. All authors have read and agreed to the published version of the manuscript. All authors reviewed the manuscript.

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Gao, H., Liu, X., Xie, L. et al. Modulation of DOM-Induced Head-Twitch Response by mGluR2 Agonist/Inverse Agonist is Associated with 5-HT2AR-Mediated Gs Signaling Pathway. Neurochem Res 49, 636–648 (2024). https://doi.org/10.1007/s11064-023-04055-y

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